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Post-hypoglycemic Hyperglycemia Are Highly Relevant Markers for Stratification of Glycemic Variability and Partial Remission Status of Pediatric Patients With New-onset Type 1 Diabetes

Antoine A. Harvengt, Olivier G. Polle, Manon Martin, Aline van Maanen, Laurent Gatto, Philippe A. Lysy

Abstract

To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not.

Introduction

Type 1 diabetes mellitus is characterized by a progressive decline in β-cell mass, resulting in a clinical state of insulinopenia when β-cell function drops below twenty percent [1], which defines the clinical disease onset. From that moment, patients with type 1 diabetes rely on a combination of exogenous insulin administration, healthy diet and regular physical activity to achieve optimal glycemic control [2–4]. Immediately after disease onset and insulin therapy initiation, the majority of patients (occurrence rate: [40–75%]) experience a period of partial remission defined by the coexistence of low levels of glycemic variability and reduced exogenous insulin requirements [5].

Materials and method

GLUREDIA is a prospective study that includes data from the multicentric DIATAG (DIAbetes TAGging)study that was previously described [21]. Briefly, DIATAG included new-onset pediatric patients with type 1 diabetes aged between 6 months and 18 years old. Type 1 diabetes was diagnosed using International Society for Pediatric and Adolescent Diabetes (ISPAD) criteria [1] and patients were positive for at least one anti-islet autoantibody (i.e., anti-insulin, anti- protein tyrosine phosphatase, anti-glutamic acid decarboxylase, anti-Zinc transporter 8). All participants and their parents gave their written consent before enrolment in the study.

Results

Seventy-one pediatric patients with new-onset type 1 diabetes were quarterly followed during the first year after diagnosis, corresponding to a total of 244 outpatient visits. Of these visits, 52 were excluded as they did not fulfill our pre-established quality criteria or had missing associated clinical data. Final analysis was performed on 192 clinical visits from 66 patients (i.e., 59 patients at +3, 48 patients at +6, 45 patients at +9 and 40 patients at 12 months after the diagnosis) representing a total of 1900000 interstitial glucose values.

Discussion

Partial remission reflects a transient recovery of β-cell function with increased insulin secretion [31] and improved peripheral insulin sensitivity [32], leading to decreased dependence on exogenous insulin and optimal glycemic control (e.g., TIR70-180, glycemia variability) [1]. When β-cell function further declines, insulin requirements and glycemic variability increase, corresponding to the end of partial remission and an increased hypoglycemic risk. Current definitions and biomarkers used to identify partial remission (i.e., residual secretion [33,34] or IDAA1C score [24]) either require invasive blood sampling or present several limitations to describe the evolution of glycemic homeostasis (e.g., hypoglycemia, glycemic variability, insulin sensitivity) [20]. In this context, there is a need for minimal-invasive reliable markers that allow the characterization and stratification of patients with type 1 diabetes based on their glycemic status.

Conclusions

In conclusion, our study provides a user-friendly software that automatically identifies and characterizes PHH glycemic patterns on CGM data in patients with new-onset type 1 diabetes. Parameters of PHH demonstrated strong correlations with routine markers of glucose homeostasis (e.g., TIR70-180, TAR>180) and glycemic variability (e.g., CV), but only moderate correlation with residual β-cell secretion estimates. These parameters distinguished remitters from non-remitters (e.g., PHH/Hyperglycemia duration ratio and PHHAUC), supporting PHH as new minimal invasive markers of PR. We believe that integrating PHH parameters in continuous glucose monitoring reports may rise awareness on hypoglycemia and foster patient-specific therapeutic interventions (e.g., management of carbohydrate intake).

Citation: Harvengt AA, Polle OG, Martin M, van Maanen A, Gatto L, Lysy PA (2023) Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes. PLoS ONE 18(11): e0294982. https://doi.org/10.1371/journal.pone.0294982

Editor: Aleksandra Klisic, University of Montenegro-Faculty of Medicine, MONTENEGRO

Received: December 6, 2022; Accepted: November 14, 2023; Published: November 30, 2023

Copyright: © 2023 Harvengt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The clinical data used in this study cannot be publicly released due to ethical and legal considerations. Researchers interested in accessing these data are requested to contact the UCLouvain Legal and Intellectual Property Department. To obtain access, a data transfer contract must be drawn up in accordance with the procedures available at the following address: https://uclouvain.be/fr/repertoires/entites/rjur.

Funding: Grant funding from Leona M. and Harry B. Helmsley Charitable Trust the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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